Catalysis using phosphine oxide compounds

ABSTRACT

Phosphine oxide compounds were used with transition metals, preferably palladium and nickel, to produce biaryls and arylamines via cross-coupling reactions with aryl halides and arylboronic acids, aryl Grignard reagents or amines.

This is a continuation-in-part of application Ser. No. 09/451,150 filedNov. 30, 1999, now U.S. Pat. No. 6,124,462

FIELD OF INVENTION

The invention relates to the use of phosphine oxide compounds complexedwith transition metals to produce biaryls and arylamines viacross-coupling reactions with aryl halides and arylboronic acids, arylGrignard reagents, or amines.

BACKGROUND

Chelating phosphine compounds when bound to metal atoms are generallyknown to be useful as catalysts. One reaction which uses palladiumphosphine catalysts is the coupling of aryl halides with amines for theproduction of arylamines, as reviewed by Hartwig, SYNLETT, 1997, (4),pg. 329-340. An example of this reaction is the coupling ofchlorobenzene and piperidine to form N-phenylpiperidine:

Another reaction in which palladium/phosphine catalysts have been usedis the Suzuki reaction, where biaryls are produced through the couplingof arylboronic acids and aryl halides, as reviewed by Suzuki, A, J.Orgmet. Chem., 576 (1999), pg. 147. One example of this reaction is thepreparation of biphenyl from phenylboronic acid and chlorobenzene:

Both of these products are important classes of compounds widely used inthe manufacture of pharmaceuticals, advanced materials, liquid polymersand ligands, and much work has been done on their preparation. However,there is an expanding need for stable, easily prepared catalysts thatresult in good yields and mild reaction conditions.

Preparation of new ligands has traditionally been performed one at atime after tedious synthesis and purification protocols. Combinatorialtechniques have greatly accelerated the discovery of new ligands, butnew synthetic schemes are needed. One valuable technique usessolid-phase supports. This solid-phase protocol allows reactions on apolymer-bound scaffold to be driven to completion by using largeexcesses of reagents in solution that can be easily filtered away fromthe polymer support. After the scaffold has been modified, an additionalcleavage step then frees the small molecule from the polymer supportinto solution for isolation.

Phosphine oxide compounds and libraries have been prepared using polymerscaffolds in U.S. application Ser. No. 09/415,347 (U.S. Ser. No.99/23509) which is incorporated in its entirety by reference. Lacking isa process for the convenient preparation of stable arylamines of theformula R¹—NR²R³ or biaryls of the formula R¹-R⁶ using a stablephosphine catalyst under mild conditions and producing good yields.

SUMMARY OF THE INVENTION

This invention is directed to the use of phosphine oxide compoundscomplexed with transition metals to produce biaryls and arylamines viacross-coupling reactions with aryl halides and arylboronic acids oramines.

More specifically, the invention is directed to a process to preparearylamines of the formula R¹—NR²R³ comprising contacting an amine of theformula HNR²R³ with an aryl compound of the formula R¹—X in the presenceof a catalytic amount of a coordination compound comprising one or moretransition metals complexed to a phosphine oxide ligand of the formulaHP(O)R⁴R⁵; wherein X is a halogen; R¹ is an optionally substituted aryl;R² and R³ are independently selected from the group consisting ofhydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino,alkoxy, aryloxy, and heterocyclic, and optionally R² and R³ can togetherform a ring; and R⁴ and R⁵ are independently selected from the groupconsisting of hydrocarbyl, substituted hydrocarbyl, heterocyclic,organometallic, Cl, Br, I, SQ₁, OQ₂, PQ₃Q₄, and NQ₅Q₆, where Q₁, Q₂, Q₃,Q₄, Q₅, and Q₆ are independently selected from the group consisting ofhydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino,alkoxy, aryloxy, and heterocyclic, and optionally R⁴ and R⁵ can togetherform a ring.

Preferably, R¹ is an optionally substituted phenyl, and the transitionmetal is selected from Periodic Group VIII. More preferably, R⁴ and R⁵are independently selected from the group consisting of hydrocarbyl,substituted hydrocarbyl and heterocyclic, the transition metal is Pd,and R² and R³ are selected from the group consisting of hydrogen,optionally substituted aryl, and wherein R² and R³ are hydrocarbyl andtogether form a ring. Most preferably X is Cl, R¹ is selected from thegroup consisting of phenyl, 4-methylphenyl, 4-methoxyphenyl, and4-trifluoromethylphenyl; R² and R³ are selected from the groupconsisting of hydrogen, phenyl, 4-methylphenyl, and together form apiperidyl ring; and R⁴ and R⁵ are selected from the group consisting oft-butyl, phenyl, i-propyl, and 2,4-methoxyphenyl.

The invention is further directed to a process to prepare biaryls of theformula R¹-R⁶ comprising contacting a boronic acid of the formulaR⁶—B(OH)₂ with an aryl compound of the formula R¹—X in the presence of acatalytic amount of a coordination compound comprising one or moretransition metals complexed to a phosphine oxide ligand of the formulaHP(O)R⁴R⁵ wherein X is a halogen; R¹ is an optionally substituted aryl;R⁶ is selected from the group consisting of hydrocarbyl, substitutedhydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic; and R⁴and R⁵ are independently selected from the group consisting ofhydrocarbyl, substituted hydrocarbyl, heterocyclic, organometallic, Cl,Br, I, SQ₁, OQ₂, PQ₃Q₄, and NQ₅Q₆, where Q₁, Q₂, Q₃, Q₄, Q₅, and Q₆ areindependently selected from the group consisting of hydrogen,hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy,and heterocyclic, and optionally R⁴ and R⁵ can together form a ring.

Preferably R¹ is an optionally substituted phenyl, and the transitionmetal is selected from Periodic Group VIII. More preferably R⁴ and R⁵are independently selected from the group consisting of hydrocarbyl,substituted hydrocarbyl and heterocyclic, the transition metal is Pd,and R⁶ is an optionally substituted aryl. Most preferably X is Cl, R¹ isselected from the group consisting of of phenyl, 4-methoxyphenyl,2-methoxyphenyl and 4-methylphenyl; R⁶ is selected from the groupconsisting of 4-methoxyphenyl, and phenyl; and R⁴ and R⁵ are selectedfrom the group consisting of t-butyl, phenyl, i-propyl, and2,4-methoxyphenyl.

The invention is further directed to a process to prepare biaryls of theformula R¹-R⁷ comprising contacting a Grignard reagent of the formulaR⁷—MgX with an aryl compound of the formula R¹—X in the presence of acatalytic amount of a coordination compound comprising one or moretransition metals complexed to a phosphine oxide compound of the formulaHP(O)R⁴R⁵, wherein X is a halogen; R¹ is an optionally substituted aryl;R⁷ is selected from the group consisting of hydrocarbyl, substitutedhydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic; and R⁴and R⁵ are independently selected from the group consisting ofhydrocarbyl, substituted hydrocarbyl, heterocyclic, organometallic, Cl,Br, I, SQ₁, OQ₂, PQ₃Q₄, and NQ₅Q₆, where Q₁, Q₂, Q₃, Q₄, Q₅, and Q₆ areindependently selected from the group consisting of hydrogen,hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy,and heterocyclic, and optionally R⁴ and R⁵ can together form a ring.

Preferably R¹ is an optionally substituted phenyl, and the transitionmetal is selected from Periodic Group VIII. More preferably R⁴ and R⁵are independently selected from the group consisting of hydrocarbyl,substituted hydrocarbyl and heterocyclic, the transition metal is Ni,and R⁷ is an optionally substituted aryl. Most preferably X is Cl, R¹ isselected from the group consisting of 4-chloroanisole and chlorobenzene;R⁷ is o-tolyl; and R⁴ and R⁵ are t-butyl.

Further, the invention includes the method of using phosphine oxides asligands for homogeneous catalysis of arylamines of the formula R¹—NR²R³or biaryls of the formula R¹-R⁶ or biaryls of the formula R¹-R⁷comprising (1) preparing a coordination compound comprising one or moretransition metals complexed to a phosphine oxide compound of the formulaHP(O)R⁴R⁵, wherein X is a halogen; R¹ is an optionally substituted aryl;R⁶ and R⁷ are independently selected from the group consisting ofhydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy,and heterocyclic; and R⁴ and R⁵ are independently selected from thegroup consisting of hydrocarbyl, substituted hydrocarbyl, heterocyclic,organometallic, Cl, Br, I, SQ₁, OQ₂, PQ₃Q₄, and NQ₅Q₆, where Q₁, Q₂, Q₃,Q₄, Q₅, and Q₆ are independently selected from the group consisting ofhydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino,alkoxy, aryloxy, and heterocyclic, and optionally R⁴ and R⁵ can togetherform a ring; and (2) contacting either (i) a boronic acid of the formulaR⁶—B(OH)₂ or (ii) an amine of the formula HNR²R³ or (iii) a Grignardreagent of the formula R⁷—MgX with an aryl compound of the formula R¹—Xin the presence of a catalytic amount of the coordination compoundprepared in step (1) to form, respectively, arylamines of the formulaR¹—NR²R³ or biaryls of the formula R¹-R⁶.

DETAILED DESCRIPTION OF THE INVENTION

This disclosure sets out methods for the use of phosphine oxidecompounds complexed with transition metals to produce biaryls andarylamines via cross-coupling reactions with aryl halides andarylboronic acids or amines. Phosphine oxides were not previously usedas ligands in homogeneous catalysis, primarily because the P-atoms donot have coordinated atoms with lone-pair electrons which wereconsidered essential.

The processes of the instant invention are an improvement over similarprocesses in the art. The phosphine oxide compounds used in the instantprocesses are air-stable solids and are easily handled, and can beeasily synthesized in a variety of forms using the methods described inU.S. patent application Ser. No. 09/415,347 (U.S. Ser. No. 99/23509).The processes are easily adapted to combinatorial procedures and can beused to construct libraries of biaryls and arylamines, which arethemselves widely used in the manufacture of pharmaceuticals, advancedmaterials, liquid polymers and as ligands. Two examples of compounds orderivatives thereof that could be made by these processes are thesynthetic dye Quinizarin Green and p-aminobiphenyl, used as anantioxidant.

Phosphine Oxide Compounds and Libraries

Phosphine oxide compounds of the formula HP(O)R⁴R⁵ are known to exist intwo tautomeric forms:

The phosphine oxide compounds can be prepared by any method. One suchmethod is via the use of polymer scaffolds as described in U.S.application Ser. No. 09/415,347 (U.S. Ser. No. 99/23509), hereinincorporated by reference. This scheme comprises the steps of contacting(i) a phosphine selected from the group consisting of XPR⁴R⁵ andHP(═O)R⁴R⁵, wherein X is a halogen, and R⁴ and R⁵ are independentlyselected from the group consisting of hydrocarbyl, substitutedhydrocarbyl and heterocyclic, organometallic, Cl, Br, I, SQ₁, OQ₂, PQ₃Q₄and NQ₅Q₆, when Q₁, Q₂, Q₃, Q₄, Q₅ and Q₆ are independently selectedfrom the group consisting of hydrogen, hydrocarbyl, substitutedhydrocarbyl, hydrocarbyl amino, alkoxy, aryloxy, and heterocyclic, andoptionally R⁴ and R⁵ can together form a ring, with (ii) a solidsupport, resulting in at least one P in the phosphine attachedindirectly or directly to the solid support via one or more covalentbonds, and optionally replacing one or more of R⁴ and R⁵ with any otherR⁴ and R⁵ defined above.

Virtually any solid material may be used as a support to prepare thephosphine oxide compounds provided it meets the following criteria:

The material is insoluble in organic, aqueous, or inorganic solvents.Organic polymer supports are acceptable in this regard but theygenerally need to be crosslinked. Inorganic support, such as metaloxides (SiO₂, Al₂O₃, TiO₂, ZrO₂, etc.), clays, and zeolites, andmodified carbons are generally insoluble in these solvents and also maybe used as supports.

The support contains reactive sites, which can be used for the covalentattachment of the phosphorus.

The reactive sites are isolated to prevent additional crosslinkingduring further chemical transformations.

The reactive sites are exposed to the reaction medium. With a polymerresin support this is achieved through the use of a resin which swellsin a reaction solvent or is sufficiently porous to allow transport ofthe reaction medium through the polymer matrix.

The term solid support refers to a material having a rigid or semi-rigidsurface that contains or can be derivatized to contain functionality,which covalently links a compound to the surface thereof. Othermodifications may be made in order to achieve desired physicalproperties. Such materials are well known in the art and include, by wayof example, polystyrene supports, polyacrylamide supports,polyethyleneglycol supports, metal oxides such as silica, and the like.Such supports will preferably take the form of small beads, pellets,disks, films, or other conventional forms, although other forms may beused.

A preferred solid support is an organic or inorganic polymer to whichthe phosphorus can be covalently attached through a side chain orpendant group of the polymeric backbone. The polymer may be crosslinkedor modified. Suitable preferred polymers useful in the preparation of asupported phosphine compound or a combinatorial library of supportedphosphine compounds includes polyolefins, polyacrylates,polymethacrylates, and copolymers thereof that meet the general criteriadescribed above. A more preferred polymeric support is polystyrenewherein the phosphorus is attached to a pendant phenyl group on thepolystyrene backbone. Most preferred is polystyrene, crosslinked withdivinylbenzene. Specifically, polystyrenes commonly used for solid phasesynthesis have been used. These particular resins are crosslinked withfrom 1 to 10 wt % divinylbenzene. The styrene moieties are substitutedin the para or meta positions. Only a portion of the styrene moietiesare substituted, typically resulting in functional group loadings ofapproximately 0.2 to 2.0 mmole per gram of resin, although this valuemay be higher or lower.

A combinatorial library of phosphine oxides can be used in the instantinvention as well as single compounds. To create a library, one or morephosphines are reacted with one or more solid supports, generating aplurality of supported phosphine compounds. Alternatively, a library maybe created by reacting one supported phosphine compound with a pluralityof cleaving agents, as described below.

As used herein, a combinatorial library is an intentionally createdcollection of a plurality of differing molecules which can be preparedby selected synthetic means and screened for a desired activity orcharacteristic in a variety of formats (e.g., libraries of solublemolecules, libraries of compounds attached to resin beads, silica chips,or other solid supports). The libraries are generally prepared such thatthe compounds are in approximately equimolar quantities, and areprepared by combinatorial synthesis. Combinatorial synthesis refers tothe parallel synthesis of diverse compounds by sequential additions ofmultiple choices of reagents which leads to the generation of largechemical libraries containing related molecules having moleculardiversity. Screening methods for libraries vary greatly and aredependent upon a desired activity, the size of library, and the class ofcompounds in the library.

The libraries can be of any type. These types include but are notlimited to arrays and mixtures. Arrays are libraries in which theindividual compounds are simultaneously synthesized in spatiallysegregated locations, typically identified by their location on a grid.Mixture libraries contain a mixture of compounds that are simultaneouslysynthesized and assayed. Identification of the most active compound isthen performed by any of several techniques well known in thecombinatorial art, such as deconvolution. (Proc. Natl. Acad. Sci. USA,91, pg. 10779 (1994)).

A preferred solid support for the combinatorial libraries of the instantinvention is an organic or inorganic polymer as described above, towhich the phosphorus can be covalently attached through a side chain orpendant group of the polymeric backbone.

One scheme used in attaching the P to the solid support is via thereaction of the halogen or hydrogen bonded to the phosphorus in thephosphine with a nucleophilic group that is covalently attached to asolid support. The term nucleophilic group is well recognized in the artand refers to chemical moieties having a reactive pair of electrons.This scheme can easily be adapted for combinatorial synthesis.

Examples of reactions to prepare the phosphine oxide compounds are shownbut not limited to those in Scheme 1 below, where SS is the solidsupport, X is a halogen, M is any metal, R can be one or more of R⁴ orR⁵ as defined above, Z is a divalent attaching group covalently attachedto at least one phosphorus in the phosphine, selected from the groupconsisting of hydrocarbylene, substituted hydrocarbylene, —O—, —S—, and—NR′—, where R′ is selected from the group consisting of anoptionally-substituted hydrocarbyl and halogen, and the Z, O, S, and Nsubstituents are covalently attached to the solid support.

Any of the substituents in the above compounds may be replaced by otherfunctional groups using any procedure known in the art. One or all ofthe substituents can be reacted in a single reaction, depending on thechoice of reactants and reaction conditions. These reactions can easilybe adapted for combinatorial processes. Examples of suitable proceduresare shown by but not limited to those depicted in Scheme 2 below, whereX, and M are as defined above, and R indicates any of R⁴ or R⁵, asdefined above. Examples of suitable definitions for M include Mg, Li,and Zn. Cp indicates a cyclopentadienyl ring.

The phosphine oxide compounds are formed by cleaving the compound fromthe solid support by contacting the supported phosphine with a compoundof the Formula ER″, wherein E is an electrophilic group and R″ isselected from the group consisting of hydrogen, hydrocarbyl, substitutedhydrocarbyl, heterocycle, organometal, Cl, Br, I, SQ₁, OQ₂, PQ₃Q₄, andNQ₅Q₆, where Q₁, Q₂, Q₃, Q₄, Q₅, and Q₆ are independently selected fromthe group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl,hydrocarbylamino, alkoxy, aryloxy, and heterocycle. R″ can be optionallyreplaced by any of R⁴ or R⁵. To create a library, one or more supportedphosphines are reacted with one or more compounds of the Formula ER″,generating a plurality of phosphine compounds.

In the above process, E is any electrophilic group that will cleave thecovalent bond attaching the phosphorus to the solid support. The termelectrophilic group is a term well recognized in the art and refers tochemical moieties, which can accept a pair of electrons from anucleophilic group as defined above. Suitable electrophilic groupsinclude H, trimethylsilyl, PCl₂, halogens, and protons donated fromcompounds such as acids, alcohols, or amines.

In the instance where ER″ is water, the resulting POH group wouldrearrange to yield to form the phosphine oxide compounds used in theinstant invention. These compounds can also be formed from any otherphosphine of the formula RPR⁴R⁵ via the replacement of R with an —OHgroup using any method known in the art. An equivalent rearrangementoccurs when a PSH group is present.

Another method for preparing the phosphine oxide compounds is to preparea phosphine oxide attached to the solid support, as explained above,then to cleave the phosphine oxide directly from the solid support.

After cleavage from the solid support, R⁴ and R⁵ may be replaced withany other substituent using any method known in the art, in order toprepare a further range of compounds, such as those described inEncyclopedia of Inorganic Chemistry (John Wiley & Sons, Vol. 6, pg.3149-3213).

Reactions of Amines with Aryl Halides to Prepared Arylamines of theFormula NHR²R³

A process is described to prepare arylamines of the formula R¹—NR²R³comprising contacting an amine of the formula HNR²R³ with an arylcompound of the formula R¹—X in the presence of a catalytic amount of acoordination compound comprising one or more transition metals complexedto a phosphine oxide compound of the formula HP(O)R⁴R⁵.

In this process, X is a halogen, R¹ is an optionally substituted arylradical, R² and R³ are independently selected from the group consistingof hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino,alkoxy, aryloxy, and heterocyclic, and optionally R² and R³ can togetherform a ring, and R⁴ and R⁵ are independently selected from the groupconsisting of hydrocarbyl, substituted hydrocarbyl, heterocyclic,organometallic, Cl, Br, I, SQ₁, OQ₂, PQ₃Q₄ and NQ₅Q₆, where Q₁, Q₂, Q₃,Q₄, Q₅ and Q₆ are independently selected from the group consisting ofhydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino,alkoxy, aryloxy, and heterocyclic, and optionally R⁴ and R⁵ can togetherform a ring. Optionally, the process can be performed intramolecularly;i.e. the amine functionality and the aryl functionality are both locatedon the same compound and the process results in a cyclization.

The amine and the aryl compound can be prepared by any method, includingany of the well-known processes in the art.

“Coordination compound” refers to a compound formed by the union of ametal ion (usually a transition metal) with a non-metallic ion ormolecule called a ligand or complexing agent.

The transition metals are defined as metals of atomic number 21 through83. Preferably, the transition metal is from Periodic Group VIII(defined as Fe, Co, Ni, Ru, Rh, Pd, Os, Ir, and Pt). More preferred isPd and Ni. The complex can be made by any synthetic method known in theart, either through direct reaction or via the use of a transition metalprecursor.

The phosphine oxide compound is prepared as disclosed above. Thephosphine oxide used in the instant invention can exist in eithertautomeric form when present as a component of the complex. The complexcan be isolated and purified before use, or be prepared and used insitu. Many of these techniques are described in Hartley, F. R. (Ed),“Chem. Met. -Carbon Bond”, 1987, vol. 4, pp. 1163-1225).

By hydrocarbyl is meant a straight chain, branched or cyclic arrangementof carbon atoms connected by single, double, or triple carbon to carbonbonds and/or by ether linkages, and substituted accordingly withhydrogen atoms. Such hydrocarbyl groups may be aliphatic and/oraromatic. Examples of hydrocarbyl groups include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, t-butyl, cyclopropyl, cyclobutyl,cyclopentyl, methylcyclopentyl, cyclohexyl, methyl-cyclohexyl, benzyl,phenyl, o-tolyl, m-tolyl, p-tolyl, xylyl, vinyl, allyl, butenyl,cyclohexenyl, cyclooctenyl, cyclooctadienyl, and butynyl. Examples ofsubstituted hydrocarbyl groups include methoxy, phenoxy, toluyl,chlorobenzyl, fluoroethyl, p-CH₃—S—C₆H₅, 2-methoxy-propyl, and(CH₃)₃SiCH₂.

By aryl is meant an aromatic carbocyclic group having a single ring(e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensedrings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), which isoptionally mono-, di-, or trisubstituted with, e.g., halogen, loweralkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,aryl, heteroaryl, and hydroxy. By aryl is also meant heteroaryl groupswhere heteroaryl is defined as 5-, 6-, or 7-membered aromatic ringsystems having at least one hetero atom selected from the groupconsisting of nitrogen, oxygen and sulfur. Examples of heteroaryl groupsare pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl,oxazolyl, furanyl, quinolinyl, isoquinolinyl, thiazolyl, and thienyl,which can optionally be substituted with, e.g., halogen, lower alkyl,lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl,heteroaryl, and hydroxy.

A preferred process is where R¹ is an optionally substituted phenyl, R⁴and R⁵ are independently selected from the group consisting ofhydrocarbyl, substituted hydrocarbyl and heterocyclic, and where R² andR³ are selected from the group consisting of hydrogen, optionallysubstituted aryl, and where R² and R³ are hydrocarbyl and together forma ring. More preferred is where X is Cl, R¹ is selected from the groupconsisting of phenyl, 4-methylphenyl, 4-methoxy-phenyl and4-trifluoromethylphenyl, R² and R³ are selected from the groupconsisting of hydrogen, phenyl, 4-methylphenyl, and together form apiperidyl ring, and R⁴ and R⁵ are selected from the group consisting oft-butyl, phenyl, i-propyl, and 2,4-methoxyphenyl. Also preferably, thetransition metal is from Periodic Group VIII. More preferred is Pd.

Reactions of Arylboronic Acids with Aryl Halides to Prepare Biaryls ofthe Formula R¹-R⁶

The instant invention also describes a process to prepare biaryls of theformula R¹-R⁶ comprising contacting a boronic acid of the formulaR⁶—B(OH)₂ with an aryl compound of the formula R¹—X in the presence of acatalytic amount of a coordination compound comprising one or moretransition metals complexed to a phosphine oxide compound of the formulaHP(O)R⁴R⁵; where X is a halogen, R¹ is an optionally substituted aryl,R⁶ is selected from the group consisting of hydrocarbyl, substitutedhydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic, and R⁴and R⁵ are independently selected from the group consisting ofhydrocarbyl, substituted hydrocarbyl, heterocyclic, organometallic, Cl,Br, I, SQ₁, OQ₂, PQ₃Q₄, and NQ₅Q₆, where Q₁, Q₂, Q₃, Q₄, Q₅, and Q₆ areindependently selected from the group consisting of hydrogen,hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy,and heterocyclic, and optionally R⁴ and R⁵ can together form a ring.Optionally, the process can be performed intramolecularly; i.e., theboronic acid functionality and the aryl functionality are both locatedon the same compound and the process results in a cyclization.

A preferred process is where R¹ is an optionally substituted phenyl, R⁴and R⁵ are independently selected from the group consisting ofhydrocarbyl, substituted hydrocarbyl and heterocyclic, and where R⁶ isan optionally substituted aryl. More preferred is where X is Cl, R¹ isselected from the group consisting of of phenyl, 4-methoxyphenyl,2-methoxyphenyl and 4-methylphenyl; R⁶ is selected from the groupconsisting of 4-methoxyphenyl, and phenyl; and R⁴ and R⁵ are selectedfrom the group consisting of t-butyl, phenyl, i-propyl, and2,4-methoxyphenyl. Also preferably, the transition metal is fromPeriodic Group VIII. More preferred is Pd.

Reactions of Aryl Grignards with Aryl Halides to Prepare Biaryls of theFormula R¹-R⁶

The instant invention also describes a process to prepare biaryls of theformula R¹-R⁷ comprising contacting a Grignard reagent of the formulaR⁷—MgX with an aryl compound of the formula R¹—X in the presence of acatalytic amount of a coordination compound comprising one or moretransition metals complexed to a phosphine oxide compound of the formulaHP(O)R⁴R⁵; where X is a halogen, R¹ is an optionally substituted aryl,R⁷ is selected from the group consisting of hydrocarbyl, substitutedhydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic, and R⁴and R⁵ are independently selected from the group consisting ofhydrocarbyl, substituted hydrocarbyl, heterocyclic, organometallic, Cl,Br, I, SQ₁, OQ₂, PQ₃Q₄, and NQ₅Q₆, where Q₁, Q₂, Q₃, Q₄, Q₅, and Q₆ areindependently selected from the group consisting of hydrogen,hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy,and heterocyclic, and optionally R⁴ and R⁵ can together form a ring.Optionally, the process can be performed intramolecularly; i.e., theGrignard functionality and the aryl functionality are both located onthe same compound and the process results in a cyclization.

A preferred process is where R¹ is an optionally substituted phenyl, R⁴and R⁵ are independently selected from the group consisting ofhydrocarbyl, substituted hydrocarbyl and heterocyclic, and where R⁷ isan optionally substituted aryl. More preferred is where X is Cl, R¹ isselected from the group consisting of 4-chloroanisole and chlorobenzene,R⁷ is o-tolyl, and R⁴ and R⁵ are t-butyl. Also preferably, thetransition metal is from Periodic Group VIII. More preferred is Ni.

Schemes 1 and 2 to form phosphine oxides, the cleaving procedures, andthe coupling reactions disclosed above are preferably performed underdry, inert atmosphere with dry, deoxygenated solvents. Any solvent issuitable provided that it is inert to all reagents and products.Suitable temperatures for homogeneous catalysis range from −80° C. to200° C. Preferred temperatures are about 0° C. to about 150° C. Exceptfor the Grignard coupling, preferably a base should be added in thecoupling reactions disclosed. Preferred bases are CsF, CsCO₃, andNaOtBu.

The following non-limiting Examples are meant to illustrate theinvention but are not intended to limit it in any way.

Materials and Methods

All manipulations of air-sensitive materials were carried out withrigorous exclusion of oxygen and moisture in flame-dried Schlenk-typeglassware on a dual manifold Schlenk line, interfaced to a high-vacuum(10⁻⁴-10⁻⁵ Torr) line, or in a nitrogen-filled Vacuum Atmospheresglovebox with a high-capacity recirculator (1-2 ppm of O₂). Before use,all solvents were distilled under dry nitrogen over appropriate dryingagents (such as sodium benzophenone ketyl and metal hydrides except forchlorinated solvents). Deuterium oxide, THF-D₈, C₆D₆ and chloroform-dwere purchased from Cambridge Isotopes (Andover, Mass.). All organic andinorganic starting materials were purchased from Aldrich Chemical Co.(Milwaukee Wis.), Farchan Laboratories Inc. (Gainesville, Fla.), StremChemicals (Newburyport, Mass.), Calbiochem-NovaBiochem Corp. (San Diego,Calif.), Rieke Metals, Inc. (Lincoln, Neb.), or Lancaster Synthesis Inc.(Windham, N.H.), and when appropriate were distilled prior to use.

List of abbreviations dba Bis(dibenzylideneacetone) DVB DivinylbenzeneGC/MS Gas chromatography/mass spectroscopy FT Fourier transform h Houri.d Inner diameter in. Inch Me Methyl mg milligram NMR Nuclear magneticresonance tBu tert-butyl

Physical and Analytical Measurements

NMR spectra were recorded on either a Nicolet NMC-300 wide-bore (FT, 300MHz, ¹H; 75 MHz, ¹³C, 121 MHz ³¹P), or GE QM-300 narrow-bore (FT, 300MHz, ¹H) instrument. Chemical shifts (δ) for ¹H, ¹³C are referenced tointernal solvent resonances and reported relative to SiMe₄. ³¹P NMRshifts are reported relative to external phosphoric acid. Analytical gaschromatography was performed on a Varian Model 3700 gas chromatographwith FID detectors and a Hewlett-Packard 3390A digitalrecorder/integrator using a 0.125 in. i.d. column with 3.8% w/w SE-30liquid phase on Chromosorb W support. GC/MS studies were conducted on aVG 70-250 SE instrument with 70 eV electron impact ionization.

The polymer bound monophosphines were prepared as described in U.S.patent application Ser. No. 09/415,347 (U.S. Ser. No. 99/23509). Thefunctional groups on the phosphines can be added in two steps to yieldunsymmetrical substitutions, or in one step to yield more symmetricalsubstitution.

A solution of t-butylamine (276 g, 3.78 moles) and KI (0.3 g, 2 mmol) in1000 mL of THF was treated with chloromethylpolystyrene-divinylbenzene(Merrifield resin, 2% DVB, 75 g, 1.26 mmol/g, 94.5 mmol) while stirringat room temperature for 30 min. The suspension was then refluxed for 24h before the solution was filtered off. The resulting resin was washedwith H₂O (3×250 mL), THF (3×150 mL), then hexane (3×200 mL). Afterdrying in vacuum overnight, 75 g of the resin were obtained (98% yieldaccording to N elemental analysis. Anal. calculated forpolymer-NHC(Me)₃: N, 1.25. Found: N, 1.22). Also the disappearance of ¹Hresonances of polymer-Ph—CH₂—Cl (CH₂═˜4.5 ppm) and the appearance of ¹Hresonances of polymer-Ph—CH₂—NHC(Me)₃ (CH₂═˜3.7 ppm) indicates that thechloromethyl groups were completely transformed to tert-butylaminometylgroups. Hereafter this will be referred to as Resin I.

A solution of PCl₃ (26 g, 189 mmol) in 400 mL of THF was treated slowlywith Resin I from above (25 g, 1.21 mmol/g, 30.3 mmol) while stirring atroom temperature for a period of 30 min. before Et₃N (16 g, 157.5 mmol)was added. The resulting suspension was stirred at room temperatureovernight before the solution was filtered off. The resin was washedwith hexane (2×50 mL), CH₂Cl₂ (5×80 mL), and hexane (5×30 mL). Theresulting polymer-bound PCl₃ resin was dried in vacuum overnight. ³¹PNMR (122 MHz, CDCl₃): δ 179.1 ppm.

A suspension of the polymer-bound PCl₂ resin from above (5.0 g, 1.12mmol/g, 5.6 mmol) in 150 mL of THF was treated slowly withphenylmagnesium bromide (2 M solution in diethylether, 64 mmol). Theresulting mixture was stirred at room temperature for 30 min. before thesolution was filtered off and the resin was washed with THF (3×50 ml),Me₂CHOH/THF (20% Me₂CHOH, 10 mL), hexane (3×30 mL). The resulting resinwas dried in vacuum overnight to yield polymer-bound PPh₂. ³¹P NMR (122MHz, CDCl₃): δ 52.3 ppm.

A solution of Cl₂PPh (33.8 g, 189 mmol) and Et₃N (16.0 g, 157.5 mmol) in500 mL of THF was treated slowly with Resin I (25.0 g, 1.21 mmol/g, 30.3mmol) while stirring at room temperature for a period of 10 min. Theresulting suspension was stirred at room temperature overnight beforethe solution was filtered off. The resin was washed with THF (50 mL),hexane (3×50 mL), CH₂Cl₂ (4×50 mL), and hexane (2×50 mL). The resultingpolymer-bound PPhCl resin was dried in vacuum overnight. ³¹P NMR (122MHz, CDCl₃): δ 135.4 ppm.

A suspension of the resulting resin, the polymer-bound PPhCl, (5.0 g,1.03 mmol/g, 5.2 mmol) in 150 mL of THF was treated slowly withi-propylmagnesium chloride (0.5 M solution in diethylether, 32.0 mmol).The resulting mixture was stirred at room temperature for 2 h before thesolution was filtered off and the resin was washed with THF (3×10 mL),Me₂CHOH/THF (20% Me₂CHOH, 5 mL), hexane (3×30 mL). The resulting resinwas dried in vacuum overnight to afford polymer-bound (i-C₃H₇)PPh. ³¹PNMR (122 MHz, CDCl₃): δ 55.5 ppm.

The following Experiments illustrate the preparation of the phosphineoxide catalyst used in the method.

EXPERIMENT 1 Synthesis of (Me₂CH)PH(O)(Ph)

A suspension of polymer-bound PPh(CHMe₂) prepared as described above(1.25 g, 1.02 mmol/g, 1.28 mmol, ³¹P NMR (121 MHz, CDCl₃): δ 55.5 ppm)and H₂O (0.1 g, 4.8 mmol) in THF (10 mL) was refluxed overnight beforethe resin was filtered off and washed with THF (2×5 mL). The filtratewas dried under vacuum to remove the solvent and excess H₂O. Theresulting residue was 80 mg (37% yield) of (Me₂CH)PH(O)(Ph). It was >95%pure by ¹H NMR and GC/MS. ³¹P NMR (121 MHz, CDCl₃, ¹H-decoupled): δ47.8. ³¹p NMR (121 MHz, CDCl₃, ¹H-coupled): δ 47.8 (d, J_(p-H)=487.7Hz). ¹H NMR (500 MHz, CDCl₃): δ 7.74-7.53 (m, 5H), 7.25 (d,J_(p-H)=487.5 Hz, 1H), 2.33 (m, 1H), 1.12 (m, 6H). ¹³C NMR (125 MHz,CDCl₃): δ 133.8, 131.1, 129.4, 125.4, 28.0, 14.7. HRMS: Calculated forC₉H₁₃PO(M⁺): 168.0704. Found: 168.0704.

EXPERIMENT 2 Synthesis of (Me₃C)PH(O)(CMe₃)

A solution of (Me₃C)₂PCl (3.0 g, 16.6 mmol, Aldrichl) in 5.0 mL ofCH₂Cl₂ was treated with H₂O (0.5 g, 27.8 mmol) over a period of 5 min.The resulting reaction mixture was stirred at room temperature for anadditional 30 min. Removal of solvent and excess H₂O afforded 2.45 g(91% yield) of (Me₃C)PH(O)(CMe₃). It was >95% pure by ¹H NMR and GC/MS.The pure product was obtained by sublimation (ca. 130° C./10⁻³ torr),³¹P NMR (121 MHz, CDCl₃, ¹H-decoupled): δ 69.8 ppm. ³¹P NMR (121 MHz,CDCl₃, ¹H-coupled): δ 69.8 (d, J_(p-H)=434.2 Hz). ¹H NMR (500 MHz,CDCl₃): δ 5.96 (d, J_(P-H)=434.7 Hz, 1H), 1.14 (d, J_(p-H)=156.4 Hz,18H). ¹³C NMR (125 MHz, CDCl₃): δ 33.8 ppm 14 (d, J_(P-C)=58.0 Hz), 25.6ppm. MS: Calculated for C₈H₁₉PO(M⁺): 162.1. Found: 163.4 (M⁺+H).

EXPERIMENT 3 Synthesis of 2-PH(O)(i-Pr)-1, 5-(MeO)₂C₆H₃

A solution of PBr₃ (2.5 g, 9.2 mm) in 15 niL of pyridine was treatedwith 1,3-dimethoxybenzene (2.5 g, 18.1 mm) over a period of 5 min. Theresulting mixture was then refluxed for 4 h to give the crude 1-dibromophosphino-2,4-dimethoxybenzene (³¹P NMR: δ 159.2 ppm). Thiscompound was used directly for the next step without furtherpurification. Next, polymer-supported secondary amines (10.0 g, 1.1mmol/g, 11.0 mmol) was slowly added into the mixture above whilestirring at room temperature for a period of 10 min. The resultingsuspension was stirred at room temperature overnight before the solutionwas filtered off. The resin was washed with THF (50 mL), hexane (3×50mL), CH₂Cl₂ (4×50 mL), and hexane (2×50 mL). The resulting resin wasdried in vacuum overnight to yield the polymer-supported P(Br)-2,4-(MeO)₂—C₆H₃. ³¹P NMR (122 MHz, CDCl₃): δ 153.8 ppm.

A suspension of this polymer-bound compound (2.0 g, 1.82 mmol, 0.908mm/g) and I-PrMgBr (12.0 mmol, 1.0 M in THF solution) in 10 mL of THFwas refluxed overnight before the solution was filtered off. Theresulting resin was washed with THF (3×20 mL), CH₂Cl₂ (3×10 mL), Me₂CHOH(2×10 mL), THF/H₂O (70/30 volume ratio, 2×20 mL) and hexane (3×10 mL).The resin was dried in vacuumn overnight. 31P NMR (122 MHz, CDCl₃): δ60.7 ppm.

A suspension of polymer-bound P(i-Pr)-2, 4-(MeO)₂—C₆H₃ (2.0 g, 1.876mmol, 0.938 mm/g) and H₂O (0.5 g, 28 mm) in 10 mL of THF was refluxedovernight before the resin was filtered off and washed with hexane (3×10mL). Removal of solvents and excess H₂O from the filtrates by vacuumafforded 100 mg (23% yield) of P(i-Pr)-2, 4-(MeO)₂—C₆H₃. It was >95%pure by ¹H NMR and GC/MS. ³¹P NMR (202 MHz, CDCl₃): δ 35.8 (s) ppm. ³¹PNMR (¹H-coupled, 202 MHz, CDCl₃): δ 35.8 (d, J_(p-H)=485.8 Hz) ppm. ¹HNMR (500 MHz, CDCl₃): δ 7.57 (m, 1H), 7.25 (d, J_(P-H)=485.2 Hz, 1H),6.48 (m, 1H), 6.37 (m, 1H), 3.76 (d, J=15.2 Hz, 3H), 3.70 (d, J=38.7 Hz,3H), 2.18 (m, 1H), 1.12-0.81 (m, 6H). ¹³C NMR (125 MHz, CDCl₃): 165.0,161.8, 135.1, 105.6, 105.5, 98.2, 67.9, 55.6, 27.4, 14.5 ppm. MS: 229.2(M+1).

EXAMPLES

A. Reactions of Amines with Aryl Halides

Example 1

In a drybox, 14.4 mg (0.087 mmol) of (Me₃C)₂PH(O) from Experiment 2,20.0 mg (0.0218 mmol) of Pd₂(dba)₃ (dba=bis(dibenzylideneacetone)) and4.0 mL of toluene were loaded into a reactor (20 mL) equipped with amagnetic stir bar. The resulting mixture was stirred at room temperatureovernight. Next, 144 mg (1.5 mmol) of NaOtBu was added into the mixtureabove, followed by syringing 122 μl (1.2 mmol) of PhCl, and 100 μl (1.0mmol) of piperidine into the reactor. The resulting mixture was refluxedfor 5 h. The reaction mixture was then cooled to room temperature,chromatographed on silicon gel using ethyl acetate/hexane (5% volumeratio) as eluant. The eluate was concentrated by rotary evaporationfollowed by high vacuum to yield 82 mg (51% yield) ofN-phenylpiperidine. It was >95% pure by ¹H NMR and GC/MS. ¹H NMR (500MHz, CDCl₃): δ 7.15 (m, 2H), 6.84 (m, 2H), 6.72 (m, 1H), 3.06 (t, J=5.48Hz, 4H), 1.61 (m, 4H), 1.48 (m, 2H) ppm. ¹³C NMR (125 MHz, CDCl₃): d152.3, 129.0, 119.2, 116.5, 50.7, 25.9, 24.4 3 ppm. MS: Calculated forC₁₁H₁₅N(M⁺): 161.3. Found: 162.3 (M⁺+H).

Example 2

The general procedure from Example 1 was followed using4-chlorobenzotrifluoride (650 mg, 3.6 mmol) and piperidine (258 mg, 3.0mmol) with Pd₂(dba)₃ (55 mg, 0.081 mmol) and (Me₃C)₂PH(O) (21.0 mg,0.126 mmol) and NaOtBu (432 mg, 4.5 mmol) in 6.0 mL of toluene. After 48h, the reaction mixture was chromatographed with 5% ethyl acetate/hexaneto give 161 mg (23% yield) of 4-piperidinobenzotrifluoride. It was >95%pure by ¹H NMR and GC/MS. ¹H NMR (500 MHz, CDCl₃): δ 7.36 (d, J=8.78 Hz,2H), 6.82 (d, J=8.79 Hz, 2H), 3.18 (m, 4H), 1.60 (m, 4H), 1.54 (m, 2H)ppm. ¹³C NMR (125 MHz, CDCl₃): d 153.7, 127.6, 126.3, 114.5, 49.2, 25.4,24.2 ppm. MS: Calculated for C₁₂H₁₄F₃N(M⁺): 229.1. Found: 230.2 (M⁺+H).

Example 3

The general procedure from Example 1 was followed using chlorobenzene(135 mg, 1.2 mmol) and aniline (93 mg, 1.0 mmol) with Pd₂(dba)₃ (25 mg,0.027 mmol) and (Me₃C)₂PH(O) (7.0 mg, 0.042 mmol) and NaOtBu (144 mg,1.5 mmol) in 2.0 mL of toluene. After 24 h, the reaction mixture waschromatographed with 5% ethyl acetate/hexane to give 51 mg (30% yield)of diphenylamine. It was >95% pure by ¹H NMR and GC/MS. ¹H NMR (500 MHz,CDCl₃): δ 7.18 (m, 4H), 6.99 (d, J=7.68 Hz, 4H), 6.84 (t, J=7.34 Hz,2H), 5.59 (br, 1H) ppm. ¹³C NMR (125 MHz, CDCl₃): d 143.1, 129.3, 120.9,117.8 ppm. MS: Calculated for C₁₂H₁₁N(M⁺): 169.1. Found: 170.3 (M⁺+H).

Example 4

The general procedure from Example 1 was followed using chlorobenzene(135 mg, 1.2 mmol) and piperidine (86 mg, 1.0 mmol) with Pd₂(dba)₃ (20mg, 0.0218 mmol) and (Me₂CH)PH(O)(Ph) from Experiment 1, (7.1 mg, 0.0424mmol) and NaOtBu (144 mg, 1.5 mmol) in 2.0 mL of 1,2-dimethoxyethane.After 5 h, the reaction mixture was chromatographed with 5% ethylacetate/hexane to give 17 mg (11% yield) of 4-phenylpiperidine. Itwas >95% pure by ¹H NMR and GC/MS. ¹H NMR (500 MHz, CDCl₃): δ 7.15 (m,2H), 6.84 (m, 2H), 6.72 (m, 1H), 3.06 (t, J=5.48 Hz, 4H), 1.61 (m, 4H),1.48 (m, 2H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ 152.3, 129.0, 119.2,116.5, 50.7, 25.9, 24.4 3 ppm. MS: Calculated for C₁₁H₁₅N(M⁺): 161.3.Found: 162.3 (M⁺+H).

Example 5

The general procedure from Example 1 was followed using4-methylchlorobenzene (152 mg, 1.2 mmol) and piperidine (100 μl, 1.0mmol) with Pd₂(dba)₃ (20 mg, 0.0218 mmol) and (Me₃C)₂PH(O) (14.5 mg,0.0878 mmol) and NaOtBu (144 mg, 1.5 mmol) in 3.0 mL of toluene. After12 h, the reaction mixture was chromatographed with 5% ethylacetate/hexane to give 106 mg (61% yield) ofN-(4-methylphenyl)piperidine. It was >95% pure by ¹H NMR and GC/MS. ¹HNMR (500 MHz, CDCl₃): δ 6.92 (d, J=8.4 Hz, 2H), 6.72 (d, J=8.5 Hz, 2H),2.95 (t, J=5.5 Hz, 4H), 2.13 (s, 3H), 1.58 (m, 4H), 1.43 (m, 2H) ppm.¹³C NMR (125 MHz, CDCl₃): δ 150.3, 129.5, 128.6, 116.9, 51.2, 25.9,24.3, 20.3 ppm. MS: Calculated for C₁₂H₁₇N(M⁺): 175.1. Found: 176.1(M⁺+H).

Example 6

The general procedure from Example 1 was followed using PhCl (122 μl,1.2 mmol) and p-toluidine (108 mg, 1.0 mmol) with Pd₂(dba)₃ (20 mg,0.0218 mmol) and (Me₃C)₂PH(O) (14.5 mg, 0.0878 mmol) and NaOtBu (144 mg,1.5 mmol) in 3.0 mL of toluene. After 12 h, the reaction mixture waschromatographed with 5% ethyl acetate/hexane to give 80 mg (44% yield)of N-phenyl-p-toluidine. It was >95% pure by ¹H NMR and GC/MS. ¹H NMR(500 MHz, CDCl₃): δ 7.13 (t, J=7.91 Hz, 2H), 6.98 (m, 2H), 6.89 (m, 4H),6.78 (t, J=7.32 Hz, 1H), 5.46 (s, br. 1H), 2.20 (s, 3H) ppm. ¹³C NMR(125 MHz, CDCl₃): d 143.9, 140.3, 130.8, 129.8, 129.2, 120.2, 118.9,116.8, 20.6 ppm. MS: Calculated for C₁₃H₁₃N(M⁺): 183.3. Found: 184.1(M⁺+H).

Example 7

The general procedure from Example 1 was followed using 4-chloroanisole(171 mg, 1.2 mmol) and piperidine (100 μl, 1.0 mmol) with Pd₂(dba)₃ (20mg, 0.0218 mmol) and (Me₃C)₂PH(O) (14.5 mg, 0.0878 mmol) and NaOtBu (144mg, 1.5 mmol) in 4.0 mL of toluene. After 12 h, the reaction mixture waschromatographed with 5% ethyl acetate/hexane to give 128 mg (67% yield)of N-(4-methoxyphenyl)piperidine. It was >95% pure by ¹H NMR and GC/MS.¹H NMR (500 MHz, CDCl₃): δ 6.81 (d, J=9.11 Hz, 2H), 6.72 (d, J=9.11 Hz,2H), 3.65 (s, 3H), 2.92 (t, J=5.46 Hz, 4H), 1.60 (m, 4H), 1.46 (m, 2H)ppm. ¹³C NMR (125 MHz, CDCl₃): δ 153.5, 146.8, 118.6, 114.3, 55.4, 52.2,26.1, 24.1 ppm.

Example 8

In the drybox, 20.0 mg (0.087 mmol) of (Me₂CH)PH(O)(2,4-(MeO)₂C₆H₃) fromExperiment 3, 20.0 mg (0.0218 mmol) of Pd₂(dba)₃ and 3.0 mL of dioxanewere loaded into a reactor (20 mL) equipped with a magnetic stir bar.The resulting mixture was stirred at room temperature for 10 min. Next,144 mg (1.5 mmol) of NaOtBu was added into the mixture above, followedby syringing 122 μl (1.2 mmol) of PhCl, and 100 μl (1.0 mmol) ofpiperidine into the reactor. The resulting mixture was refluxed for 8 h.The reaction mixture was then cooled to room temperature,chromatographed on silicon gel using ethyl acetate/hexane (5% volumeratio) as eluant. The eluate was concentrated by rotary evaporationfollowed by high vacuum to yield 59 mg (37% yield) of1-phenylpiperidine. It was >95% pure by ¹H NMR and GC/MS. ¹H NMR (500MHz, CDCl₃): δ 7.15 (m, 2H), 6.84 (m, 2H), 6.72 (m, 1H), 3.06 (t, J=5.48Hz, 4H), 1.61 (m, 4H), 1.48 (m, 2H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ152.3, 129.0, 119.2, 116.5, 50.7, 25.9, 24.43 ppm. MS: Calcd forC₁₁H₁₅N(M⁺): 161.3. Found: 162.3 (M⁺+H).

The results of Examples 1-8 are summarized in Table 1 below.

TABLE 1 Example Phosphine oxide Aryl compound Amine Product Yield 1(Me₃C)₂PH(O) chlorobenzene piperidine 1-phenylpiperidine 51% 2(Me₃C)₂PH(O) 4-chlorobenzotrifluoride piperidine4-piperidinobenzotrifluoride 23% 3 (Me₃C)₂PH(O) chlorobenzene anilinediphenylamine 30% 4 (Me₂CH)PH(O)(Ph) chlorobenzene piperidineN-phenylpiperidine 11% 5 (Me₃C)₂PH(O) 4-methylchlorobenzene piperidineN-(4-methylphenyl)piperidine 61% 6 (Me₃C)₂PH(O) chlorobenzenep-toluidine N-phenyl-p-toluidine 44% 7 (Me₃C)₂PH(O) 4-chloroanisolepiperidine N-(4-methoxyphenyl)piperidine 67% 8(Me₂CH)PH(O)(2,4-(MeO)₂C₆H₃) chlorobenzene piperidine 1-phenylpiperidine37%

B. Reactions of Arylboronic Acids with Aryl Halides

Example 9

In the drybox, 14.4 mg (0.087 mmol) of (Me₃C)₂PH(O) from Experiment 2,20.0 mg (0.0218 mmol) of Pd₂(dba)₃ and 4.0 mL of 1,4-dioxane were loadedinto a reactor (20 mL) equipped with a magnetic stir bar. The resultingmixture was stirred at room temperature overnight. Next, 651 mg (2.0mmol) of CsCO₃ and 146.3 mg (1.2 mm) of PhB(OH)2 were added into themixture above, followed by syringing 122 μl (1.2 mmol) of PhCl into thereactor. The resulting mixture was refluxed for 24 h. The reactionmixture was then cooled to room temperature, chromatographed on silicongel using ethyl acetate/hexane (5% volume ratio) as eluant. The eluatewas concentrated by rotary evaporation followed by high vacuum to yield163 mg (88% yield) of biphenyl. It was >95% pure by ¹H NMR and GC/MS. ¹HNMR (500 MHz, CDCl₃): δ 7.77 (d, J=7.75 Hz, 4H), 7.60 (t, J=7.65 Hz,4H), 7.50 (t, J=7.38 Hz, 2H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ 141.2,128.7, 127.2, 127.1 ppm.

Example 10

The general procedure from Example 9 was followed using4-methylchlorobenzene (152 mg, 1.2 mmol) and PhB(OH)₂ (1.2 mmol) withPd₂(dba)₃ (20 mg, 0.0218 mmol) and (Me₃C)₂PH(O) from Experiment 2 (14.5mg, 0.0878 mmol) and CsCO₃ (651 mg, 2.0 mmol) in 4.0 mL of 1,4-dioxane.After 24 h, the reaction mixture was chromatographed with 5% ethylacetate/hexane to give 127 mg (63% yield) of 4-phenyltoluene. Itwas >95% pure by ¹H NMR and GC/MS. ¹H NMR (500 MHz, CDCl₃): δ 7.74 (d,J=7.50 Hz, 2H), 7.65 (d, J=8.05 Hz, 2H), 7.57 (m, 2H), 7.47 (m, 1H),7.40 (m, 2H), 2.54 (s, 3H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ 141.1,138.3, 136.9, 129.4, 128.6, 126.9, 126.8, 21.0 ppm.

Example 11

The general procedure above was followed using 4-methylchlorobenzene(127 mg, 1.0 mmol) and PhB(OH)₂ (183 mg, 1.5 mmol) with Pd₂(dba)₃ (20mg, 0.0218 mmol) and PhPH(O)(CHMe₂) from Experiment 1 (14.7 mg, 0.0874mmol) and CsF (456 mg, 3.0 mmol) in 4.0 mL of 1,4-dioxane. After 12 h,the reaction mixture was chromatographed with 5% ethyl acetate/hexane togive 52 mg (31% yield) of 4-phenyltoluene. It was >95% pure by ¹H NMRand GC/MS.

Example 12

In the drybox, 9.6 mg (0.058 mmol) of (Me₃C)₂PH(O) from Experiment 2,13.3 mg (0.0145 mmol) of Pd₂(dba)₃ and 3.0 mL of 1,4-dioxane were loadedinto a reactor (20 mL) equipped with a magnetic stir bar. The resultingmixture was stirred at room temperature overnight. Next, 143.0 mg (1.0mm) of 4-chloro-anisole, 182.9 mg (1.5 mm) of PhB(OH)₂ and 456 mg (3.0mmol) of CsF were added into the reactor. The resulting mixture wasrefluxed for 24 h. The reaction mixture was then cooled to roomtemperature, chromatographed on silicon gel using ethyl acetate/hexane(5% volume ratio) as eluant. The eluate was concentrated by rotaryevaporation followed by high vacuum to yield 179 mg (97% yield) of4-phenylanisole. It was >95% pure by ¹H NMR and GC/MS. ¹H NMR (500 MHz,CDCl₃): δ 7.45 (m, 4H), 7.32 (m, 2H), 7.21 (m, 1H), 6.88 (d, J=8.72 Hz,2H), 3.74 (s, 3H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ 159.2, 140.8, 133.8,128.7, 128.1, 126.7, 126.6, 114.2, 55.3 ppm.

Example 13

The general procedure from Example 12 was followed using 2-chloroanisole(143 mg, 1.0 mmol) and 4-MeC₆H₄B(OH)₂ (204 mg, 1.5 mmol) with Pd₂(dba)₃(13.3 mg, 0.0145 mmol) and (Me₃C)₂PH(O) from Experiment 2 (9.6 mg, 0.058mmol) and CsF (456 mg, 3.0 mmol) in 4.0 mL of 1,4-dioxane. After 24 h,the reaction mixture was chromatographed with 5% ethyl acetate/hexane togive 165 mg (83% yield) of 2-(4-methylphenyl)anisole. It was >95% pureby ¹H NMR and GC/MS. ¹H NMR (500 MHz, CDCl₃): δ 7.32 (d, J=8.06 Hz, 2H),7.18 (m, 2H), 7.10 (d, J=7.88 Hz, 2H), 6.92-6.84 (m, 2H), 3.67 (s, 3H),2.28 (s, 3H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ 156.5, 136.5, 135.6,130.7, 129.4, 128.7, 128.3, 120.8, 111.2, 55.5, 21.1 ppm.

Example 14

The general procedure from Example 12 was followed using 4-chloroanisole(143 mg, 1.0 mmol) and 4-MeOC₆H₄B(OH)₂ (228 mg, 1.5 mmol) with Pd₂(dba)₃(13.3 mg, 0.0145 mmol) and (Me₃C)₂PH(O) from Experiment 2 (9.6 mg, 0.058mmol) and CsF (456 mg, 3.0 mmol) in 3.0 mL of 1,4-dioxane. After 24 h,the reaction mixture was chromatographed with 5% ethyl acetate/hexane togive 213 mg (99% yield) of 4-(4-methoxyphenyl)anisole. It was >95% pureby ¹H NMR and GC/MS. ¹H NMR (500 MHz, CDCl₃): δ 7.38 (d, J=8.68 Hz, 4H),6.86 (d, J=8.68 Hz, 4H), 3.74 (s, 6H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ158.7, 133.5, 127.7, 114.2, 55.3 ppm.

Example 15

In the drybox, 20.0 mg (0.0876 mmol) of (Me₂CH)PH(O)(2,4-(MeO)₂C₆H₃)from Experiment 3, 20 mg (0.0218 mm) of Pd₂(dba)₃ and 5.0 mL of1,4-dioxane were loaded into a reactor (20 ml) equipped with a magneticstir bar. The resulting mixture was stirred at room temperatureovernight. Next, 143.0 mg (1.0 mm) of 4-chloroanisole, 228 mg (1.5 mm)of 4-MeOC₆H₄B(OH)₂ and 456 mg (3.0 mmol) of CsF were added into thereactor. The resulting mixture was refluxed for 60 h. The reactionmixture was then cooled to room temperature, chromatographed on silicongel using ethyl acetate/hexane (5% volume ratio) as eluant. The eluatewas concentrated by rotary evaporation followed by high vacuum to yield213 mg (99% yield) of p-(4-methoxyphenyl)anisole. It was >95% pure by ¹HNMR and GC/MS. ¹H NMR (500 MHz, CDCl₃): δ 7.38 (d, J=8.68 Hz, 4H), 6.86(d, J=8.68 Hz, 4H), 3.74 (s, 6H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ 158.7,133.5, 127.7, 114.2, 55.3 ppm. Anal Calcd for C₁₄H₁₄O₂: C, 78.48; H,6.59. Found: C, 78.44; H, 6.53.

The results of Examples 9-15 are summarized in Table 2 below.

TABLE 2 Example Phosphine oxide Aryl compound Acid Product Yield  9(Me₃C)₂PH(O) chlorobenzene PhB(OH)₂ biphenyl 88% 10 (Me₃C)₂PH(O)4-methylchlorobenzene PhB(OH)₂ 4-phenyltoluene 63% 11 PhPH(O)(CHMe₂)4-methylchiorobenzene PhB(OH)₂ 4-phenyltoluene 31% 12 (Me₃C)₂PH(O)4-chloroanisole PhB(OH)₂ 4-phenylanisole 97% 13 (Me₃C)₂PH(O)2-chloroanisole 4-MeC₆H₄B(OH)₂ 2-(4-methylphenyl)- 83% anisole 14(Me₃C)₂PH(O) 4-chloroanisole 4-MeOC₆H₄B(OH)₂ 4-(4-methoxyphenyl)- 99%anisole 15 (Me₂CH)PH(O)(2,4-(MeO)₂C₆H₃) 4-chloroanisole 4-MeOC₆H₄B(OH)₂4-(4-methoxyphenyl)- 99% anisole

Example 16

In a drybox, 50 mg (0.303 mmol) of (Me₃C)₂PH(O) from Experiment 2, 83.4mg (0.303 mmol) of Ni(COD)₂ (COD=1,5-cyclooctadiene) and 5.0 mL of THFwere loaded into a reactor (100 mL) equipped with a magnetic stir bar.The resulting mixture was stirred at room temperature over 10 min. Next,1.43 g (10.0 mmol) of 4-chloroanisole was added into the mixture above,followed by adding 15 ml (15.0 mmol, 1.0 M solution in THF) ofo-tolylmagnesium chloride, and 15 mL of THF into the reactor. Theresulting mixture was stirred at room temperature for 15 h. before thereaction mixture was quenched with 10 mL of H₂O. The mixture above wasextracted with 3×50 mL of diethyl ether. The combined ether extractswere dried over MgSO₄, filtered, and the ether and THF removed from thefiltrate by rotary evaporation. The resulting residues werechromatographed on silicon gel using ethyl acetate/hexane (5% volumeratio) as eluant. The eluate was concentrated by rotary evaporationfollowed by high vacuum to yield 1.85 g (93% yield) of 4-o-tolylanisole.It was >95% pure by ¹H NMR. ¹H NMR (500 MHz, CDCl₃): δ 7.47-7.19 (m,8H), 4.03 (s, 3H), 2.53 (s, 3H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ 158.5,141.5, 135.3, 134.3, 130.2, 130.1, 129.8, 126.8, 125.7, 113.4, 55.0,20.4. ppm.

Example 17

The general procedure from Example 16 was followed using chlorobenzene(1.126 g, 10.0 mmol) and o-tolylmagnesium chloride (15 mL, 15.0 mmol)with Ni(COD)₂ (83.4 mg, 0.303 mmol) and (Me₃C)₂PH(O) (50.0 mg, 0.303mmol) in 20.0 mL of THF. After 15 h at room temperature, the reactionmixture was quenched with 10 mL of H₂O. The mixture above was extractedwith 3×50 mL of diethyl ether. The combined ether extracts were driedover MgSO₄, filtered, and the ether and THF removed from the filtrate byrotary evaporation. The resulting residues were chromatographed onsilicon gel using ethyl acetate/hexane (5% volume ratio) as eluant. Theeluate was concentrated by rotary evaporation followed by high vacuum toyield 1.62 g (96% yield) of 2-phenyltoluene. It was >95% pure by ¹H NMR.¹H NMR (500 MHz, CDCl₃): δ 7.62-7.47 (m, 9H), 2.50 (s, 3H) ppm. ¹³C NMR(125 MHz, CDCl₃): δ 142.0, 141.9, 135.2, 130.3, 129.7, 129.1, 128.0,127.2, 126.7, 125.7, 20.4. ppm.

What is claimed is:
 1. A process to prepare biaryls of the formula R¹-R⁷comprising contacting a Grignard reagent of the formula R⁷—MgX with anaryl compound of the formula R¹—X in the presence of a catalytic amountof a coordination compound comprising one or more transition metalscomplexed to a phosphine oxide compound of the formula HP(O)R⁴R⁵,wherein X is a halogen; R¹ is an optionally substituted aryl; R⁷ isselected from the group consisting of hydrocarbyl, substitutedhydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic; and R⁴and R⁵ are independently selected from the group consisting ofhydrocarbyl, substituted hydrocarbyl, heterocyclic, organometallic, Cl,Br, I, SQ₁, OQ₂, PQ₃Q₄, and NQ₅Q₆, where Q₁, Q₂, Q₃, Q₄, Q₅, and Q₆ areindependently selected from the group consisting of hydrogen,hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy,and heterocyclic, and optionally R⁴ and R⁵ can together form a ring. 2.The process of claim 1 wherein R¹ is an optionally substituted phenyl.3. The process of claim 2 wherein the transition metal is selected fromPeriodic Group VIII.
 4. The process of claim 3 wherein R⁴ and R⁵ areindependently selected from the group consisting of hydrocarbyl,substituted hydrocarbyl and heterocyclic, and wherein the transitionmetal is Ni.
 5. The process of claim 4 wherein R⁷ is an optionallysubstituted aryl.
 6. The process of claim 5 wherein X is Cl.
 7. Theprocess of claim 6 wherein: R¹ is selected from the group consisting of4-chloroanisole and chlorobenzene; R⁷ is o-tolyl; and R⁴ and R⁵ aret-butyl.
 8. A method for the use of phosphine oxides as ligands forhomogeneous catalysis biaryls of the formula R¹-R⁷ comprising: (1)preparing a coordination compound comprising one or more transitionmetals complexed to a phosphine oxide compound of the formula HP(O)R⁴R⁵,wherein X is a halogen; R¹ is an optionally substituted aryl; R⁷ isselected from the group consisting of hydrocarbyl, substitutedhydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic; and R⁴and R⁵ are independently selected from the group consisting ofhydrocarbyl, substituted hydrocarbyl, heterocyclic, organometallic, Cl,Br, I, SQ₁, OQ₂, PQ₃Q₄, and NQ₅Q₆, where Q₁, Q₂, Q₃, Q₄, Q₅, and Q₆ areindependently selected from the group consisting of hydrogen,hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy,and heterocyclic, and optionally R⁴ and R⁵ can together form a ring; and2) contacting either a Grignard reagent of the formula R⁷—MgX with anaryl compound of the formula R¹—X in the presence of a catalytic amountof the coordination compound prepared in step (1) to form biaryls of theformula R¹-R⁷.